The present invention relates to molecular chimaeras in infective virions: methods of their construction; pharmaceutical formulations containing them; their use in therapy, particularly virus-directed enzyme prodrug therapy, particularly in the treatment of cancers, and more particularly in the treatment of hepatocellular and colorectal carcinomas; and the use of agents which can be catalysed by a heterologous enzyme to cytotoxic or cytostatic metabolites, such as purine arabinosides and substituted pyrimidines and cytosines in virus-directed enzyme prodrug therapy in a host (e.g., mammal or human).
Cancer of all forms is one of the major causes of morbidity throughout the world. Research in cancer chemotherapy has produced a variety of antitumour agents with differing degrees of efficacy. Standard clinically used agents include adriamycin, actinomycin D, methotrexate, 5-fluorouracil, cisplatin, vincristine and vinblastine. However, these presently available antitumour agents are known to have various disadvantages such as toxicity to healthy cells and resistance of certain tumour types. Other forms of therapy, such as surgery, are known. However it is appreciated by those skilled in the art that novel approaches and entities for cancer therapy are still needed.
Hepatocellular carcinoma (HCC) is one of the major malignant diseases in the world today; the greatest incidence being in Japan, China, other parts of Asia, and sub-Saharan Africa. Recent evidence suggests that the incidence of hepatocellular carcinoma in Europe and North America is increasing. The disease is estimated to be responsible for or involved in up to approximately 1,250,000 deaths a year, making it one of the world""s major malignant diseases.
The prognosis of HCC is always poor, with the worldwide frequency rate almost equalling the mortality rate. After diagnosis, the median survival time is less than four months. Long-term survival, defined as survival longer than one year after diagnosis, is seen only occasionally. Most HCC patients succumb to either the complications of liver failure with or without massive bleeding, or to the general effects of a large tumour burden, with cachexia, malnutrition, infection, and sepsis. Though distant metastases occur (up to 90% of patients have metastatic tumour at time of death), regional disease most often limits survival. Consequently, therapies directed toward control of hepatic tumours are appropriate, although it will be appreciated that treatment of the metastatic disease is also of great importance (Kew M. C. Postgrad. Med. J. 59 (Suppl. 4) 78-87 (1983) and Berk P. (Ed) Semin. Liver Dis. 4, No.2, Thieme-Stratton Inc. N.Y. (1984)).
Current therapies available to the clinician are basically ineffective as a curative treatment for this disease (Nerenstone S. R., Ihde D. C., Friedman M. A. Cancer Treat. Rev. 15, 1-31 (1988)). To date, surgery continues to be the only potentially curative treatment. However, at the time of diagnosis, the overwhelming majority of patients are not able to undergo radical surgery. In certain studies (Nerenstone et al supra) less than 3% of patients were considered capable of undergoing surgery and of the small percentage that do undergo surgery, approximately 50% suffer from postoperative morbidity (Nerenstone et al supra).
Colorectal carcinoma (CRC) is the second most frequent cancer and the second leading cause of cancer-associated deaths in the United States and Western Europe (Silverberg, E. CA 33, 9-25(1983); Silverberg, E. CA 36, 9-25(1986); Farley, P. C., and McFaden, K. H. Postgrad. Med. 84, 175-183) (1988). The overall five-year survival rate for patients has not meaningfully improved in the last three decades. Prognosis for the CRC cancer patient is associated with the depth of tumor penetration into the bowel wall, the presense of regional lymph node involvement and, most importantly, the presense of distant metastases. The liver is the most common site for distant metastasis and, in approximately 30% of patients, the sole initial site of tumor recurrence after successful resection of the primary colon cancer (Daly, J. M., and Kemeny, N. Import. Adv. Oncol. 251-286(1986)). Hepatic metastases are the most common cause of death in the CRC cancer patient (Swinton, N. W., et al., Dis. Colon Rectum 7, 273-277(1964)).
The treatment of choice for the majority of patients with hepatic CRC metastasis is systemic or regional chemotherapy using 5-fluorouracil (5-FU) alone or in combination with other agents such as leviamasole (for a review see Daly, J. M., and Kemeny, N. (1986) Import. Adv. Oncol. 251-286). However, despite extensive effort, there is still no satisfactory treatment for hepatic CRC metastasis.
Systemic single- and combination-agent chemotherapy and radiation are relatively ineffective emphasizing the need for new approaches and therapies for the treatment of these diseases.